Bottom Line:
While normal degradation of ECM components is an important feature of tissue repair and remodeling, irregular ECM turnover contributes to a variety of liver diseases.Matrix metalloproteinases (MMPs) are the main enzymes implicated in ECM degradation.MMPs not only remodel the ECM, but also regulate immune responses.

Figure 1: Schematic model for MMP-dependent liver damage after the IR-insult. The IR-insult to the liver results in MMP-dependentand independent release of ROS, cytokines, and other pro-inflammatory mediators, which activate innate immune cells and upregulate the expression of liver vascular adhesion molecules. Interactions between activated integrins (e.g. α4β1 and α5β1) expressed on leukocytes and newly synthesized adhesion molecules promote binding of leukocytes to the liver endothelium. MMPs, particularly leukocyte-derived MMP-9 (in the presence of low levels of TIMP-1), facilitate focal matrix degradation and leukocyte extravasation across vascular barriers. Besides leukocyte recruitment, MMP-mediated loss of the vascular endothelial cell barrier integrity interferes with the liver’s capability to regenerate after hepatic IRI. Additionally, MMPs contribute to tissue injury by promoting parenchyma cell detachment from ECM, resulting in apoptosis/anoikis of parenchyma cells. Pro-inflammatory factors produced during the acute phase of IRI, such as TNF-α, and iNOS-derived NO, further stimulate the production/activation of MMPs, which in turn modulate the activity of some of these factors through proteolytic cleavage; thus, providing a possible feedback loop that would amplify and sustain the inflammatory environment.

Mentions:
Focal matrix degradation during leukocyte extravasation is likely regulated by a complex interplay of proteolytic cascades. MT1-MMP/MMP-14, which is expressed by infiltrating macrophages in damaged livers, facilitates their migration through FN coated membranes, suggesting that MT1-MMP/MMP-14 may act as an amplifier in the recruitment of macrophages in hepatic IRI [52]. MMP-2, MMP-3, MMP-8, MMP-10, MMP-12, and MMP-13 are among other significantly upregulated MMPs during hepatic IRI, but very little is still known about their specific functions in the progression of acute liver damage [27,48]. (Duarte & Coito, unpublished studies) MMP mediated proteolysis may not only facilitate leukocyte migration, but may also lead to detachment of parenchyma cells from ECM resulting in apoptosis, a phenomenon called “anoikis” [53]. In this regard, hepatocyte apoptosis is significantly reduced in the absence of MMP-9 after hepatic IRI [51]. Fig. 1 illustrates MMP-dependent liver damage after the IR-insult.

Figure 1: Schematic model for MMP-dependent liver damage after the IR-insult. The IR-insult to the liver results in MMP-dependentand independent release of ROS, cytokines, and other pro-inflammatory mediators, which activate innate immune cells and upregulate the expression of liver vascular adhesion molecules. Interactions between activated integrins (e.g. α4β1 and α5β1) expressed on leukocytes and newly synthesized adhesion molecules promote binding of leukocytes to the liver endothelium. MMPs, particularly leukocyte-derived MMP-9 (in the presence of low levels of TIMP-1), facilitate focal matrix degradation and leukocyte extravasation across vascular barriers. Besides leukocyte recruitment, MMP-mediated loss of the vascular endothelial cell barrier integrity interferes with the liver’s capability to regenerate after hepatic IRI. Additionally, MMPs contribute to tissue injury by promoting parenchyma cell detachment from ECM, resulting in apoptosis/anoikis of parenchyma cells. Pro-inflammatory factors produced during the acute phase of IRI, such as TNF-α, and iNOS-derived NO, further stimulate the production/activation of MMPs, which in turn modulate the activity of some of these factors through proteolytic cleavage; thus, providing a possible feedback loop that would amplify and sustain the inflammatory environment.

Mentions:
Focal matrix degradation during leukocyte extravasation is likely regulated by a complex interplay of proteolytic cascades. MT1-MMP/MMP-14, which is expressed by infiltrating macrophages in damaged livers, facilitates their migration through FN coated membranes, suggesting that MT1-MMP/MMP-14 may act as an amplifier in the recruitment of macrophages in hepatic IRI [52]. MMP-2, MMP-3, MMP-8, MMP-10, MMP-12, and MMP-13 are among other significantly upregulated MMPs during hepatic IRI, but very little is still known about their specific functions in the progression of acute liver damage [27,48]. (Duarte & Coito, unpublished studies) MMP mediated proteolysis may not only facilitate leukocyte migration, but may also lead to detachment of parenchyma cells from ECM resulting in apoptosis, a phenomenon called “anoikis” [53]. In this regard, hepatocyte apoptosis is significantly reduced in the absence of MMP-9 after hepatic IRI [51]. Fig. 1 illustrates MMP-dependent liver damage after the IR-insult.

Bottom Line:
While normal degradation of ECM components is an important feature of tissue repair and remodeling, irregular ECM turnover contributes to a variety of liver diseases.Matrix metalloproteinases (MMPs) are the main enzymes implicated in ECM degradation.MMPs not only remodel the ECM, but also regulate immune responses.